Expiration date: 09/2025

The composition and form of issue:

Solution for subcutaneous injection. 1 ml contains:

liraglutide 6 mg

1 syringe pen (3 ml) contains 18 mg liraglutide

excipients: sodium hydrogen phosphate dihydrate propylene glycol phenol hydrochloric acid/sodium hydroxide water for injections

in syringe pens of 3 ml (30 doses of 0.6 mg, 15 doses of 1.2 mg or 10 doses of 1.8 mg) in the paper cartons 1, 2 or 3 pen.

Description pharmaceutical form:

Colorless or almost colorless clear solution.

Pharmacokinetics:

Absorption. The absorption of liraglutide after p/to the introduction is slow, Tmax in plasma is 8-12 hours after administration of the dose. Cmax of liraglutide in plasma after p/to the injections in a single dose of 0.6 mg is 9.4 nmol/l With the introduction of liraglutide dose of 1.8 mg, the average of the equilibrium concentration in the plasma (for other uses/24) reached approximately 34 nmol/l liraglutide Exposure (exposure to drug) increases proportionally to the administered dose. After the introduction of liraglutide in a single dose intra-population coefficient of variation for AUC is 11%. The absolute bioavailability of liraglutide after p/to the introduction is approximately 55%.

Distribution. The apparent volume of distribution of liraglutide in the tissue after p/to the introduction — 11-17 L. the mean volume of distribution liraglutide after in/introductions — 0.07 l/kg Liraglutide is largely associated with blood plasma proteins (>98%).

Metabolism. For 24 hours after administration to healthy volunteers a single dose of labeled radioactive isotope [3H]-liraglutide a major component of the plasma remained unchanged liraglutide. Was detected two metabolites in plasma (&le9 &le5% of the level of total radioactivity in plasma). Liraglutide is metabolized similar to endogenous large proteins, without the involvement of any specific authority as the way out.

Excretion. After dosing of [3H]-liraglutide unchanged liraglutide was not detected in urine or feces. Only a small portion of the administered radioactivity in the form of liraglutide-related metabolites (6 and 5%, respectively) were derived by the kidneys or through the intestines. Radioactive substances by the kidneys or through the intestines are excreted mainly within the first 6-8 days after administration of the dose, and represent the three metabolite. The average clearance from the body after p/to the introduction of liraglutide in a single dose is approximately 1.2 l/h with an elimination T1/2 approximately 13 hours

Special groups of patients

Older age: data from pharmacokinetic studies in healthy volunteers and analysis of pharmacokinetic data obtained in patients from 18 to 80 years, show that age has no clinically significant effect on the pharmacokinetic properties of liraglutide.

Gender: population pharmacokinetic analysis of data obtained in the study of effects of liraglutide in patients both male and female, and the data of pharmacokinetic studies in healthy volunteers indicate that gender has no clinically significant effect on the pharmacokinetic properties of liraglutide.

Ethnicity: population pharmacokinetic analysis of data obtained in the study of effects of liraglutide in subjects of white, black, Asian and Hispanic racial groups, indicates that ethnicity has no clinically significant effect on the pharmacokinetic properties of liraglutide.

Obesity: population pharmacokinetic analysis of the data suggests that the body mass index (BMI) has no clinically significant effect on the pharmacokinetic properties of liraglutide.

Hepatic impairment: the pharmacokinetic properties of liraglutide were investigated during clinical trials a single dose of the drug in subjects with varying degrees of hepatic insufficiency. The exposure of liraglutide in patients with mild and moderate hepatic insufficiency was reduced by 13-23% as compared to that in the group of healthy subjects. In patients with severe hepatic insufficiency (classified Child-Pugh a severity of illness >9 points) exposition of liraglutide was significantly lower (44%).

Renal insufficiency: in patients with renal impairment liraglutide exposure was reduced compared to that in subjects with normal renal function. Liraglutide exposure was lowered by 33, 14, 27 and 28% respectively in patients with mild (Cl creatinine 50-80 ml/min), moderate (Cl creatinine 30-50 ml/min) and severe (creatinine Cl <30 ml/min) renal insufficiency and end-stage renal failure in patients on dialysis.

Preclinical data security

The results of preclinical pharmacological studies of the introduction of repeated doses of the drug for toxicity, including genotoxicity, showed that the use of liraglutide is not posing threats to human health. Tumors of C-cells of the thyroid gland of rats and mice was identified during a two-year test of oncogenicity of the drug in rodents and did not lead to a lethal outcome. The level of non-manifested side effects (NOAEL) in rats is not observed. The appearance of such tumors in monkeys treated with liraglutide for 20 months, was observed. The results obtained in tests on rodents, due to the fact that rodents are particularly sensitive in relation to it is mediated by the receptor glucagonoma peptide-1 (GLP-1) is not a specific genotoxic mechanism. The significance of the obtained data to humans is low but cannot be completely excluded. The appearance of any other neoplasms related to treatment were noted. In tests on animals revealed no direct adverse effect of the drug on fertility, but there was a slight increase in the frequency of early embryonic death in the treatment the highest dose. The introduction of the drug Victoza rats in mid-pregnancy caused a reduction in body weight of the mother and fetal growth with a not fully understood effect on the ribs and in the group of rabbits — variations in skeletal structure. The growth of newborn individuals in a group of rats during drug therapy, Victoza declined, and this decline steadily continued in the period after the end of breastfeeding in the model group treated with high-dose liraglutide. It is unknown what caused this decline in the growth of newborn animals rats — decrease consumption of milk due to a direct effect of GLP-1, or inadequate supply of breast milk to maternal individuals of rats due to the lower consumption of calories.

Description pharmacological action:

Liraglutide is an analog of human glucagonoma peptide-1 (GLP-1), produced by the method of biotechnology recombinant DNA using a strain of Saccharomyces cerevisiae, with 97% of self with the human GLP-1 that binds and activates the receptor GLP-1 in humans. The receptor GLP-1 is a target for native GLP-1 is an endogenous hormone incretin causing glucosidation stimulation of insulin secretion in the beta cells of the pancreas. Unlike native GLP-1, pharmacokinetic and pharmacodynamic profiles of liraglutide allow you to enter his patients a daily 1 time per day.

Profile of long-acting liraglutide when s/to the injections is provided by three mechanisms: self-Association, resulting in slow absorption of the drug binding to albumin, and higher enzymatic stability towards dipeptidylpeptidase-4 (DPP-4) enzyme and neutral endopeptidase (NEP), which results in prolonged T1/2 of the drug from plasma. The effect of liraglutide is due to the interaction with specific receptors of GLP-1, resulting in increased levels of camp.

Under the action of liraglutide occurs glucosetoxicity stimulation of insulin secretion. Simultaneously, liraglutide suppresses too high glucosidation the secretion of glucagon. Thus, when the concentration of blood glucose stimulation of insulin secretion and suppression of glucagon secretion. On the other hand, during hypoglycaemia liraglutide diminishes insulin secretion but does not inhibit glucagon secretion. The mechanism of reduction of blood glucose levels also includes a small delay in gastric emptying. Liraglutide reduces body mass and reduces body fat by means of causing decrease in hunger and reduced energy consumption.

Liraglutide has a long 24-hour action and improves glycemic control by reducing the concentration of blood glucose fasting and after meals in patients with diabetes mellitus type 2.

Indications:

Drug Victoza is indicated as adjuvant in the background diet and exercise to achieve glycaemic control in patients with diabetes mellitus type 2. Drug Victoza shown as part of combination therapy to achieve glycemic control with:

Metformin or sulfonylureas in patients with insufficient glycemic control despite maximally tolerated doses of Metformin or sulfonylurea derivatives in monotherapy

Metformin and sulfonylureas, or Metformin and thiazolidinedione in patients with insufficient glycemic control despite combination therapy with two drugs.

Contraindications:

• hypersensitivity to the active substance or other components included in the composition of the drug
  
• pregnancy and period of breast-feeding (see "pregnancy and breastfeeding")
  
• diabetes mellitus type 1
  
• diabetic ketoacidosis (see "Special instructions")
  
• severe violations of kidney function
  
• the liver
  
• heart failure III–IV functional class (according to NYHA classification)
  
• inflammatory bowel disease
  
• paresis of the stomach (see "Special instructions")
  
• the age of 18 (see "Method of application and dosage").
  

With caution:

• heart failure I–II functional class (according to NYHA classification)
  
• of renal dysfunction moderate severity
  
• age 75 years and older (see "Special instructions", "the Method of application and dosage").
  

Application of pregnancy and breast-feeding:

Adequate data on the use of the drug Victoza in pregnant women. Animal studies have shown reproductive toxicity (see "Pharmacokinetics. Preclinical data security"). The potential risk for humans is unknown.

Drug Victoza cannot be used during pregnancy, instead it is recommended that treatment with insulin. If the patient is preparing for a pregnancy, or a pregnancy has occurred, therapy with the drug Victoza must cease immediately.

Unknown, selects whether liraglutide in breast milk of women. Animal studies have shown that the penetration of liraglutide and metabolites of close structural connection in breast milk is low. Experience with the use of the drug Victoza in lactating women is no. The use of the drug during lactation is contraindicated.

Side effects:

In five large long-term clinical studies involving more than 2500 patients treated with the drug Victoza as monotherapy, in combination with Metformin, sulfonylureas (in combination with Metformin /) or in combination with a combination of Metformin plus rosiglitazon. All side effects were divided into the groups according to the frequency, which is defined as: very common (&ge1/10) frequently (&GE. 1/100 to <1/10) uncommon (&ge1/1,000 to <1/100) rare (&ge1/10,000 and <1/1000) very rare (<1/10000) and not known (cannot be estimated on the basis of available data). Side effects within each group are presented in descending order of severity.

In clinical trials the most frequent side effects were disorders of the gastrointestinal tract: nausea and diarrhea — very often, vomiting, constipation, pain in abdomen and dyspepsia — often. At the beginning of therapy victoza the drug, these side effects can develop more as you continue treatment reactions usually diminish within a few days or weeks. Side effects such as headache and upper respiratory tract infections were observed frequently. Frequently mentioned was the development of hypoglycemic conditions, and very often hypoglycemia occurred when the drug Victoza in combination with sulfonylureas. Most cases of hypoglycemia occurred in the background of the combined drug Victoza with sulfonylureas.

Table 1 contains information about the side effects identified in patients during clinical trials of the drug Victoza 3rd phase. The table below presents adverse reactions with an incidence of >5%, provided that their frequency was higher in the group of patients receiving the drug Victoza, as compared to that in the group of patients receiving drugs comparison. The table also includes adverse reactions with an incidence of &ge1%, provided that their frequency was in 2 and more times higher than frequency of adverse reactions in groups of patients receiving treatment comparison.

Table 1

Adverse reactions identified during long-term placebo-controlled clinical trials 3 phase

?????? ? ???????/???????? ???????	The incidence of
Adverse reactions	Often	Very often
Metabolism and disorders of digestive system
Hypoglycemia	X
Anorexia	X
Loss of appetite	X
Violations from nervous system
Headache	X
Violations by the gastrointestinal tract
Nausea		X
Diarrhea		X
Vomiting	X
Dyspepsia	X
Pain in the upper abdomen	X
Constipation	X
Gastritis	X
Flatulence	X
Bloating	X
Gastroesophageal reflux	X
Burp	X
Infections and infestations
Infections of the upper respiratory tract	X

Drug interactions:

Evaluation of liraglutide in vitro have shown its very low ability to pharmacokinetic interaction with drugs that are metabolized by enzyme systems of cytochrome P450 (CYP) and plasma protein binding.

A small delay in gastric emptying caused by receiving liraglutide may influence absorption of concomitant medicinal products for oral use. Clinical studies of drug interactions with other drugs showed no clinically significant effect on the absorption rate of these drugs. Several patients treated with the drug Victoza, noted at least one episode of acute diarrhea. Diarrhea can affect the absorption of oral drugs that are used simultaneously with the drug Victoza.

The paracetamol. Liraglutide did not cause changes in systemic exposure of paracetamol after his admission in a single dose of 1000 mg. Cmax of paracetamol in plasma by 31%, and the average Tmax in plasma is extended by 15 minutes While receiving liraglutide and paracetamol dose adjustment of the latter is not required.

Atorvastatin. Liraglutide did not cause clinically meaningful changes in systemic exposure of atorvastatin after his introduction in a single dose of 40 mg. Therefore, dose adjustment of atorvastatin in patients receiving the drug Victoza not required. Cmax of atorvastatin in plasma decreased by 38%, and the average Tmax value of plasma in patients receiving liraglutide lengthened from 1 to 3 hours.

Griseofulvin. Liraglutide did not cause changes in systemic exposure griseofulvin after his introduction in a single dose of 500 mg griseofulvin Cmax increased by 37%, while the average Tmax value of plasma has not changed. Dose adjustments of griseofulvin and other drugs with low solubility and high permeability are not required.

Lisinopril and digoxin. The introduction of lisinopril in a single dose of 20 mg or digoxin in a single dose of 1 mg against the use of liraglutide showed a reduction of lisinopril AUC by 15% and AUC of digoxin by 16% Cmax of lisinopril was decreased by 27%, and digoxin by 31%. The average value of the Tmax of lisinopril in plasma in patients receiving liraglutide increased from 6 to 8 h, and the average value of the Tmax of digoxin in the same conditions increased from 1 to 1.5 hours Based on the results, dose adjustment of lisinopril and digoxin in patients receiving liraglutide is not required.

Oral contraceptives. Cmax of ethinyl estradiol and levonorgestrel as a single dose on the background of treatment with liraglutide decreased by 12 and 13%, respectively. Under the same conditions the average value of these drugs Tmax occurred 1.5 hours later than usual. Clinically significant effect on systemic exposure of ethinyl estradiol and levonorgestrel in the body liraglutide has not. Thus, the expected contraceptive effect of both drugs on the background of treatment with liraglutide does not change.

Warfarin. Studies on the interaction of two drugs was carried out. At the beginning of treatment Victoza in patients receiving warfarin, it is recommended that more frequent monitoring of the MHO.

Insulin. Assessment of drug interactions Victoza with insulin was conducted.

Incompatibility. Substances added to the drug Victoza may cause degradation of liraglutide. Because research on compatibility was conducted, the drug Victoza cannot be mixed with other drugs.

Method of application and dose:

P/to, in the abdomen, thigh or upper arm, 1 time a day at any time, regardless of the meal. The place and time of injection can be changed without dose adjustment. However, it is preferable to introduce the drug at approximately the same time of day, in the most convenient time for the patient. Further information on the method of application of the drug Victoza, see "guidelines for use". Drug Victoza cannot be used for/in and/m introduction.

Dose

The initial dose is 0.6 mg liraglutide daily. After treatment for at least 1 week the dose should be increased to 1.2 mg. There is evidence that in some patients the effectiveness of treatment increases with the dose from 1.2 to 1.8 mg. With the aim of achieving the best glycemic control of the patient and based on clinical efficacy the dose of the drug Victoza can be increased to 1.8 mg after application at a dose of 1.2 mg for at least 1 week. The use of the drug in a daily dose higher than 1.8 mg are not recommended.

Drug Victoza it is recommended to apply additionally to an existing therapy with Metformin or combination therapy with Metformin with thiazolidinediones. Therapy with Metformin and thiazolidindiones you can continue in the same doses.

Drug Victoza it is recommended to add to therapy sulfonylureas or combination therapy of Metformin with sulfonylureas. When you add a drug Victoza to therapy of sulfonylureas should be considered dose reduction of sulfonylureas with the aim of minimizing the risk of undesirable hypoglycemia (see "Special instructions").

For dose adjustment of the drug Victoza does not require self-monitoring of blood glucose. However, at the beginning of drug therapy, Victoza in combination with sulfonylureas, such self-monitoring of blood glucose may be required for dose adjustments of sulfonylureas.

Special groups of patients

Older age (>65 years): no dose adjustment is required depending on age. There is limited experience with the drug in patients aged 75 years and older (see "Pharmacokinetics").

Patients with renal insufficiency: no dose adjustment is required for patients suffering from renal failure easy form. There is limited experience with the drug in patients with moderate renal insufficiency. At present, the use of the drug Victoza in patients with severe renal impairment including patients with end-stage renal disease is contraindicated (see "Pharmacokinetics").